Molecular imaging is based on the selective and specific interaction of a molecular probe (e.g. a radiotracer) with a biological target (for instance a receptor, an enzyme, an ion channel or any other cellular component that is able to bind or retain the molecular probe) which is visualized through PET, nuclear magnetic resonance, near infrared or other methods. PET, a nuclear medical imaging modality, is ideally suited to produce three-dimensional images that provide important information, on the distribution of a biological target in a given organ, or on the metabolic activity of such organ or cell or on the ability of a drug to enter such organ, bind to a biological target and/or modify biological processes. Since PET is a non-invasive imaging technique it can be used to investigate the pathophysiology of a disease and the action of drug on a given molecular target or cellular processes in humans and in animals. The availability of a PET radiotracer specific for a given molecular target can facilitate drug development and the understanding of the mechanism of action of a drug. In addition, a PET radiotracer may facilitate diagnosis of a disease by demonstrating pathophysiological changes taking place as a consequence of the disease.
Glycine transporter inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of diseases states implicated are psychoses, schizophrenia (Armer R E and Miller D J, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression, associated with bipolar disorders and mood disorders, associated with schizophrenia, (Pralong E T et al., Prog. Neurobiol., 67: 173-202, 2002), autistic disorders (Carlsson M L, J. Neural Trans, 105: 525-535, 1998), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer R E and Miller D J, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001).
The human brain is a complex organ, consisting of millions of intercommunicating neurons. The understanding of abnormalities relating to diseases is the key to the future development of effective diagnosis and novel therapeutics. The study of biochemical abnormalities in humans is rapidly becoming an essential and integral component of drug discovery and development process. Traditionally, the discovery and development of new drugs has been performed with a heavy emphasis on in vitro techniques to select promising lead candidates which are subsequently tested in living animals prior to human administration. Because in vitro systems reflect only part of the complexity of living systems and in vivo animal models of human disease are often only an approximation of human pathology, there is growing realization that a robust understanding of drug-receptor interaction in living man at an early stage in this process will be a major driving force in further enhancing the efficient and timely discovery and development of novel therapeutics. Over recent years, there has been a growing use of human medical imaging to assess pathologies, disease processes and drug action. These imaging modalities include PET, MRI, CT, ultrasound, EEG, SPECT and others (British Medical Bulletin, 2003, 65, 169-177). Therefore, the use of non-invasive imaging modalities, e.g. PET is an invaluable tool for the development of drugs in the future. Non-invasive nuclear imaging techniques can be used to obtain basic and diagnostic information about the physiology and biochemistry of a variety of living subjects. These techniques rely on the use of sophisticated imaging instrumentation that is capable of detecting radiation emitted from radiotracers administered to such living subjects. The information obtained can be reconstructed to provide planar and tomographic images that reveal distribution of the radiotracer as a function of time. The use of radiotracers can result in images that contain information on the structure, function and most importantly, the physiology and biochemistry of the subject. Much of this information cannot be obtained by other means. The radiotracers used in these studies are designed to have defined behaviors in vivo which permit the determination of specific information concerning the physiology or biochemistry of the subject. Currently, radiotracers are available for obtaining useful information concerning cardiac function, myocardial blood flow, lung perfusion, liver function, brain blood flow, regional brain glucose and oxygen metabolism (WO2007/041025).
Furthermore,
PET imaging provides a non-invasive and quantitative assay of normal and abnormal neurochemistry in human at an early stage of the drug development to enhance the efficient and effective discovery of therapeutics.
Tracer doses of labeled compounds enable the early evaluation of novel drugs: bio-distribution studies; receptor occupancy studies to optimize drug-dosing regime and characterizing downstream responses of drug action.
Understanding disease mechanisms in human using non-invasive techniques is intimately connected with future developments in the diagnosis and management of diseases and of novel therapeutics.
Radionuclides commonly used in PET include 11C, 13N, 15O or 18F. In principle, it is possible to label all drugs with each of these radionuclides, but only a few are found applicable as imaging agents in vivo in humans. The radioactive half-time of 11C, 13N, 15O and 18F are 20, 10, 2 and 110 min, respectively. These short half-lives provide a number of advantages as tracers to probe biological processes in vivo using PET. For example, repeat studies in the same subject can be made within the same day. PET increasingly is being used as a tool to determine drug-dose-enzyme/receptor occupancy relationships in well-defined compounds. The use of PET radiotracers that specifically bind to the target receptor or enzyme can provide information about
the ability of a drug to enter the brain and bind to the target site,
the degree of occupancy of the target site produced by a given dose of drug,
the time-course of occupancy, and
the relative plasma and tissue kinetics of the drug in question.
Occupancy studies are performed with PET radiotracers which are usually not identical to the drug candidate under study (British Medical Bulletin, 2003, 65, 169-177).